Activation of NLRP3 inflammasome by SARS-CoV-2 (WP4876)

Homo sapiens

Orf3a from SARS-CoV has been shown to bind TRAF3 and activate the NLRP3 inflammasome. The activation occurs at two points. First, by ubiquinating NF-kB (p105) to stimulate its proteolytic processing into mature NF-kB (p50), which can then go on to promote the transcription of pro-IL-1B together with RELA (p65). And second, by ubiquitinating ASC (PYCARD) in the NLRP3 inflammasome, which leads to its degradtion and the activation of caspase-1 (CASP1) that goes on to catalyze the production of mature IL-1B, leading to a cytokine storm. While Orf3a of SARS-CoV-2 only has 72.7% sequence identity with that of SARS-CoV, the TRAF3 binding motif PxQxS is 100% conserved ( Chloroquine, a multi-functional antiviral, decreases the production of IL-1B by affecting "the processing of primary transcripts in the nucleus, the transport of processed mRNA to the cytosol, and the degradation of mRNA." (Jang 2006)


Alex Pico , Egon Willighagen , Marvin Martens , Eric Weitz , Martina Summer-Kutmon , and Nhung Pham


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Homo sapiens




Disease Ontology

severe acute respiratory syndrome COVID-19 viral infectious disease

Pathway Ontology

regulatory pathway interleukin-1 signaling pathway


Label Type Compact URI Comment
Chloroquine Metabolite wikidata:Q422438
TRAF3 GeneProduct ensembl:ENSG00000131323
NLRP3 GeneProduct ensembl:ENSG00000162711
RELA GeneProduct ensembl:ENSG00000173039
NFKB1 GeneProduct ensembl:ENSG00000109320
NFKB1 p105 GeneProduct ensembl:ENSG00000109320
IL1B GeneProduct ensembl:ENSG00000125538
pro-IL1B GeneProduct ensembl:ENSG00000125538
ASC GeneProduct ensembl:ENSG00000103490
CASP1 GeneProduct ensembl:ENSG00000137752
pro-CASP1 GeneProduct ensembl:ENSG00000137752
orf3a Protein refseq:YP_009724391


  1. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. FASEB J. 2019 Aug;33(8):8865–77. PubMed Europe PMC Scholia